Abstract

Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.

title = "The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption",

abstract = "Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.",

T1 - The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance

T2 - Application to the prediction of nasal drug absorption

AU - Inoue, Daisuke

AU - Tanaka, Akiko

AU - Kimura, Shunsuke

AU - Kiriyama, Akiko

AU - Katsumi, Hidemasa

AU - Yamamoto, Akira

AU - Ogawara, Ken ichi

AU - Kimura, Toshikiro

AU - Higaki, Kazutaka

AU - Yutani, Reiko

AU - Sakane, Toshiyasu

AU - Furubayashi, Tomoyuki

PY - 2018/5/30

Y1 - 2018/5/30

N2 - Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.

AB - Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.